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Emerging Therapies for CML

Insights From: Kendra Sweet, MD, Moffitt Cancer Center; Naval Daver, MD, University of Texas MD Anderson Cancer Center; Javier Pinilla-Ibarz, MD, PhD, Moffitt Cancer Center
Published Online: Wednesday, Apr 12, 2017



Transcript:

Javier Pinilla-Ibarz, MD, PhD:
It’s very interesting to see that in the future of the treatment of CML, there still are drugs coming in to our armamentarium. Even in the situation where we have multiple drugs to choose from and we have a very high rate, this is a very, very good situation where we have more drugs that may really fill the halls of patients who may be intolerant, may be resistant, or maybe have an advanced phase of CML. In this regard, it’s really, really a light of hope to see this drug coming to the clinical trials.

Aurora kinase inhibitors is a new family of drugs that also has potential in the future treatment of CML. What is very unclear is what really will be their role in chronic phase, considering the great success of the drugs that we have available. However, I think we still need to introduce drugs that may control a more advanced phase of CML, the accelerated phase or blast phase; situations that with the current drugs, we still don’t have a very, very high success.

ABL001 is a very interesting drug that is in the development phase at this point. What is very interesting is that it does not bind to the classical ATP binding pocket that all other TKIs have as their main mechanism of action. However, it is binding to another side of the BCR-ABL protein, in this case, of the ABL protein that is involved in the 3D confirmation of this gene, of this protein. Seems like there are very, very interesting data in cell lines and also in the phase I trial where we have seen important efficacy of this drug. I think in the future, we’re going to see more how this drug may be able to be developed even as a single agent or in combinations in patients who already fail other tyrosine kinase inhibitors.

Naval Daver, MD: In general, about 90% to 92% of patients with CML, especially those who present in chronic-phase CML, will have a very durable, quick, major molecular, as well as cytogenic, remission to an appropriately selected second-generation tyrosine kinase inhibitor and also to a first-generation tyrosine kinase inhibitor in about 80% to 85% of cases. So, the majority of CML patients respond very, very well. However, there is a subset, about 5% to 8%, who could either have a very delayed acquisition of a major molecular remission or a complete molecular remission. About 3% to 5% may actually have baseline-resistant ABL kinase mutations that make them resistant to a primary therapy. And then, there’s a third subset of patients who have a durable major or a complete molecular remission for a few years, but then lose it. The reasons they could lose it are either because they become noncompliant or it could be because they have become resistant by acquisition of the secondary mutation.

So, in those cases, I think we’re looking at new exploratory options with combinations. One of the combinations I can mention is adding interferon to dasatinib, and there are some early data that suggest this could eradicate the molecular clones and produce deeper remissions, especially since it’s being evaluated in patients who have had a tyrosine kinase inhibitor and are progressing. Some of the other combinations that we, at our center, are excited about in a clinical trial format are combining JAK inhibitors. We have seen in patients who either do not achieve a complete molecular, or major molecular, response that when we add back a JAK inhibitor, we’re able to get them into complete molecular remission in small subsets.

The 2 others that I think would be very exciting are adding immune checkpoint–based drugs, such as nivolumab. There is a study of dasatinib plus nivolumab in patients who have been on a TKI for more than 1 year without achieving a complete molecular or a major molecular response to see if we could activate the T cells to push down the responses. And there is rationale in CML that there may be overexpression of PD-1 on T cells. This has been shown by different investigators. By using a PD-1 inhibitor, we could increase the T-cell activity against the CML cells.

We think that these are probably ongoing. It’s very early to know if they’re going to show clear benefit. And they’re all being tried mainly in the setting of patients who are resistant or relapsed after 1 or 2 TKIs. So, I think we’re at least a few years away from trying to bring these into the frontline, and I think for now, the second-generation TKIs up front are the standard.

Javier Pinilla-Ibarz, MD, PhD: In the last year, the field of chronic myeloid leukemia and the therapy with tyrosine kinase has been a very successful area where we have multiple tyrosine kinase inhibitors, which are very successful in the frontline and even in the second-line setting. Of course, introduction of second-generation TKIs has changed the paradigm to really obtain this early molecular response and open the possibility to increase the number of patients that really are able to be part of these already real-time treatment discontinuation trials. We have been studying this for 5 years, but I think the most important thing that we are really experiencing in 2017 is the fact that now, it’s a reality, it’s not at trials anymore. We start to discuss this discontinuation with patients that we’ve been following 3, 4, 5, or even 10 years in our practices who may really still experience these chronic side effects and still may have what we call “financial toxic side effects.” And this is really what everyone is excited about in the world of CML. Of course, in the future, I think one of the goals, and one of the hopes, is to try to see how we’re going to even increase the number of patients who can be safely discontinued, if not with a single TKI, then after additional drugs, as we see this year with ruxolitinib or even the data with interferon-alpha, which may increase the population of patients who are really free of drugs for a long period of time.

Transcript Edited for Clarity
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Transcript:

Javier Pinilla-Ibarz, MD, PhD:
It’s very interesting to see that in the future of the treatment of CML, there still are drugs coming in to our armamentarium. Even in the situation where we have multiple drugs to choose from and we have a very high rate, this is a very, very good situation where we have more drugs that may really fill the halls of patients who may be intolerant, may be resistant, or maybe have an advanced phase of CML. In this regard, it’s really, really a light of hope to see this drug coming to the clinical trials.

Aurora kinase inhibitors is a new family of drugs that also has potential in the future treatment of CML. What is very unclear is what really will be their role in chronic phase, considering the great success of the drugs that we have available. However, I think we still need to introduce drugs that may control a more advanced phase of CML, the accelerated phase or blast phase; situations that with the current drugs, we still don’t have a very, very high success.

ABL001 is a very interesting drug that is in the development phase at this point. What is very interesting is that it does not bind to the classical ATP binding pocket that all other TKIs have as their main mechanism of action. However, it is binding to another side of the BCR-ABL protein, in this case, of the ABL protein that is involved in the 3D confirmation of this gene, of this protein. Seems like there are very, very interesting data in cell lines and also in the phase I trial where we have seen important efficacy of this drug. I think in the future, we’re going to see more how this drug may be able to be developed even as a single agent or in combinations in patients who already fail other tyrosine kinase inhibitors.

Naval Daver, MD: In general, about 90% to 92% of patients with CML, especially those who present in chronic-phase CML, will have a very durable, quick, major molecular, as well as cytogenic, remission to an appropriately selected second-generation tyrosine kinase inhibitor and also to a first-generation tyrosine kinase inhibitor in about 80% to 85% of cases. So, the majority of CML patients respond very, very well. However, there is a subset, about 5% to 8%, who could either have a very delayed acquisition of a major molecular remission or a complete molecular remission. About 3% to 5% may actually have baseline-resistant ABL kinase mutations that make them resistant to a primary therapy. And then, there’s a third subset of patients who have a durable major or a complete molecular remission for a few years, but then lose it. The reasons they could lose it are either because they become noncompliant or it could be because they have become resistant by acquisition of the secondary mutation.

So, in those cases, I think we’re looking at new exploratory options with combinations. One of the combinations I can mention is adding interferon to dasatinib, and there are some early data that suggest this could eradicate the molecular clones and produce deeper remissions, especially since it’s being evaluated in patients who have had a tyrosine kinase inhibitor and are progressing. Some of the other combinations that we, at our center, are excited about in a clinical trial format are combining JAK inhibitors. We have seen in patients who either do not achieve a complete molecular, or major molecular, response that when we add back a JAK inhibitor, we’re able to get them into complete molecular remission in small subsets.

The 2 others that I think would be very exciting are adding immune checkpoint–based drugs, such as nivolumab. There is a study of dasatinib plus nivolumab in patients who have been on a TKI for more than 1 year without achieving a complete molecular or a major molecular response to see if we could activate the T cells to push down the responses. And there is rationale in CML that there may be overexpression of PD-1 on T cells. This has been shown by different investigators. By using a PD-1 inhibitor, we could increase the T-cell activity against the CML cells.

We think that these are probably ongoing. It’s very early to know if they’re going to show clear benefit. And they’re all being tried mainly in the setting of patients who are resistant or relapsed after 1 or 2 TKIs. So, I think we’re at least a few years away from trying to bring these into the frontline, and I think for now, the second-generation TKIs up front are the standard.

Javier Pinilla-Ibarz, MD, PhD: In the last year, the field of chronic myeloid leukemia and the therapy with tyrosine kinase has been a very successful area where we have multiple tyrosine kinase inhibitors, which are very successful in the frontline and even in the second-line setting. Of course, introduction of second-generation TKIs has changed the paradigm to really obtain this early molecular response and open the possibility to increase the number of patients that really are able to be part of these already real-time treatment discontinuation trials. We have been studying this for 5 years, but I think the most important thing that we are really experiencing in 2017 is the fact that now, it’s a reality, it’s not at trials anymore. We start to discuss this discontinuation with patients that we’ve been following 3, 4, 5, or even 10 years in our practices who may really still experience these chronic side effects and still may have what we call “financial toxic side effects.” And this is really what everyone is excited about in the world of CML. Of course, in the future, I think one of the goals, and one of the hopes, is to try to see how we’re going to even increase the number of patients who can be safely discontinued, if not with a single TKI, then after additional drugs, as we see this year with ruxolitinib or even the data with interferon-alpha, which may increase the population of patients who are really free of drugs for a long period of time.

Transcript Edited for Clarity
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